ABSTRACT High plasma HIV-1 RNA concentrations are associated with increased risk of HIV-1 transmission. Initiation of antiretroviral therapy (ART) reduces plasma HIV-1 concentrations. We aimed to assess the effect of ART use by patients infected with HIV-1 on risk of transmission to their uninfected partners.
Participants in our prospective cohort analysis were from a randomised placebo-controlled trial that enrolled heterosexual African adults who were seropositive for both HIV-1 and herpes simplex virus type 2, and their HIV-1 seronegative partners. At enrolment, HIV-1 infected participants had CD4 counts of 250 cells per microL or greater and did not meet national guidelines for ART initiation; during 24 months of follow-up, CD4 counts were measured every 6 months and ART was initiated in accordance with national guidelines. Uninfected partners were tested for HIV-1 every 3 months. The primary outcome was genetically-linked HIV-1 transmission within the study partnership. We assessed rates of HIV-1 transmission by ART status of infected participants.
3381 couples were eligible for analysis. 349 (10%) participants with HIV-1 initiated ART during the study, at a median CD4 cell count of 198 (IQR 161-265) cells per microL. Only one of 103 genetically-linked HIV-1 transmissions was from an infected participant who had started ART, corresponding to transmission rates of 0.37 (95% CI 0.09-2.04) per 100 person-years in those who had initiated treatment and 2.24 (1.84-2.72) per 100 person-years in those who had not-a 92% reduction (adjusted incidence rate ratio 0.08, 95% CI 0.00-0.57, p=0.004). In participants not on ART, the highest HIV-1 transmission rate (8.79 per 100 person-years) was from those with CD4 cell counts lower than 200 cells per microL. In couples in whom the untreated HIV-1 infected partner had a CD4 cell count greater than 200 cells per microL, 66 (70%) of 94 transmissions occurred when plasma HIV-1 concentrations exceeded 50 000 copies per mL.
Low CD4 cell counts and high plasma HIV-1 concentrations might guide use of ART to achieve an HIV-1 prevention benefit. Provision of ART to HIV-1 infected patients could be an effective strategy to achieve population-level reductions in HIV-1 transmission.
Bill & Melinda Gates Foundation; US National Institutes of Health.

[Show abstract][Hide abstract]ABSTRACT:
Early diagnosis of human immunodeficiency virus (HIV) allows for appropriately timed interventions with improved outcomes, but HIV screening among asymptomatic persons and the general population in Singapore remains low. In 2008, Singapore's Ministry of Health implemented HIV voluntary opt-out screening (VOS) for hospitalised adults. We evaluated the outcome of VOS and surveyed reasons for its low uptake in our institution.
We assessed the outcomes of the VOS programme from January 2010 to December 2013 at National University Hospital, a 1081-bed tertiary hospital in Singapore. We also examined reasons for opting-in and opting-out using an interviewer-administered structured questionnaire in a representative sample in January 2013.
107,523 patients fulfilled VOS criteria and were offered HIV screening, of which 5215 (4.9%) agreed to testing. 4850 (93.1%) of those who opted-in had an HIV test done. Three (0.06%) tested positive for HIV. 238 patients (14.2%) were surveyed regarding reasons for opting-in or out of VOS. 21 (8.8%) had opted-in. Patients who opted-in were likely to be younger, more educated and reported having more regular sexual partners. Type of housing, number of casual sexual partners, sexual orientation, intravenous drug use, condom use and previous sexually transmitted infection were not associated with deciding to opt-in/out. Patients' most common reasons for opting-out were: belief that they were at low risk (50.2%), belief that they were too old (26.8%), cost (6.9%) and aversion to venepuncture (6.5%). The most common reason for opting-in was desire to know their HIV status (47.6%).
The success of an HIV-VOS program is largely determined by test uptake. Our study showed that the majority of eligible VOS patients opted-out of HIV screening. Given the considerable cost and low yield of this programme, more needs to be done to better equip patients in self-risk assessment and opting in to testing.

[Show abstract][Hide abstract]ABSTRACT:
Persons with unsuppressed HIV viral load (VL) who disengage from care may experience poor clinical outcomes and potentially transmit HIV. We assessed the feasibility and yield of using the San Francisco Department of Public Health (SFDPH) enhanced HIV surveillance system (eHARS) to identify and re-engage such persons in care.
Using SFDPH eHARS data as of 4/20/2012 (index date), we selected HIV-infected adults who were alive, had no reported VL or CD4 cell count results in the past nine months (proxy for "out-of-care") and a VL >200 copies/mL drawn nine to 15 months earlier. We prioritized cases residing locally for investigation, and used information from eHARS and medical and public health databases to contact them for interview and referral to the SFDPH linkage services (LINCS). Twelve months later, we matched-back to eHARS data to assess how HIV laboratory reporting delays affected original eligibility, and if persons had any HIV laboratory results performed and reported within 12 months after index date ('new labs').
Among 434 eligible persons, 282 were prioritized for investigation, of whom 75 (27%) were interviewed, 79 (28%) could not be located, and 48 (17%) were located out of the area. Among the interviewed, 54 (72%) persons accepted referral to LINCS. Upon match-back to eHARS data, 324 (75%) in total were confirmed as eligible, including 221 (78%) of the investigated; most had new labs.
Among the investigated persons presumed out-of-care, we interviewed and offered LINCS referral to about one-quarter, demonstrating the feasibility but limited yield of our project. Matching to updated surveillance data revealed that a substantial minority did not disengage from care and that most re-engaged in HIV care. Verifying persons' HIV care status with medical providers and improving timeliness of transfer and cross-jurisdictional sharing of HIV laboratory data may aid future efforts.

[Show abstract][Hide abstract]ABSTRACT:
HIV voluntary counseling and testing (VCT) utilization remains low in many sub-Saharan African countries, particularly in remote rural settings. We sought to identify factors associated with service awareness and service uptake of VCT among female heads of household in rural Zambézia Province of north-central Mozambique which is characterized by high HIV prevalence (12.6%), poverty, and suboptimal health service access and utilization.
Our population-based survey of female heads of household was administered to a representative two-stage cluster sample using a sampling frame created for use on all national surveys and based on census results. The data served as a baseline measure for the Ogumaniha project initiated in 2009. Survey domains included poverty, health, education, income, HIV stigma, health service access, and empowerment. Descriptive statistics and logistic regression were used to describe service awareness and service uptake of VCT.
Of 3708 women surveyed, 2546 (69%) were unaware of available VCT services. Among 1162 women who were aware of VCT, 673 (58%) reported no prior testing. In the VCT aware group, VCT awareness was associated with higher education (aOR = 2.88; 95% CI = 1.61, 5.16), higher income (aOR = 1.41, 95% CI = 1.06, 1.86), higher numeracy (aOR = 1.05, CI 1.03, 1.08), more children < age 5 in the home (aOR = 1.53; 95% CI = 1.07, 2.18), closer proximity to a health facility (aOR = 1.05; 95% CI = 1.03, 1.07), and mobile phone ownership (aOR = 1.37; 95% CI = 1.03, 1.84) (all p-values < 0.04). Having a higher HIV-associated stigma score was the factor most strongly associated with being less likely to test. (aOR = 0.41; 95% CI = 0.23, 0.71; p<0.001).
Most women were unaware of available VCT services. Even women who were aware of services were unlikely to have been tested. Expanded VCT and social marketing of VCT are needed in rural Mozambique with special attention to issues of community-level stigma reduction.

Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed.
The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual
current impact factor.
Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence
agreement may be applicable.

did not meet country guidelines for ART initiation; during follow-up, CD4 counts were measuredevery 6 months and ART initiated following national guidelines. HIV-1 uninfected partners weretested for HIV-1 every 3 months. We compared genetically-linked HIV-1 transmission rates byART initiation.Results—349 (10%) HIV-1 infected partners initiated ART, at a median CD4 count of 198 cells/mm3. Only one of 103 linked HIV-1 transmissions was observed from an HIV-1 infected partnerwho had initiated ART corresponding to HIV-1 transmission rates of 0.37 versus 2.24 per 100person-years for those who had initiated versus not initiated ART, respectively (adjusted incidencerate ratio 0.08, 95% confidence interval 0.002–0.57, p=0.004). After ART initiation, plasmaHIV-1 RNA concentrations decreased significantly (from median 4.88 to <2.38 log10 copies/mL,p<0.001) as did unprotected sex (6.2% of visits before to 3.7% of visits after ART initiation,p=0.03). Among those not on ART, the highest HIV-1 transmission rate (8.79 per 100 person-years) was from HIV-1 infected persons with CD4 counts <200 cells/mm3. In couples in which theHIV-1 infected partner had a CD4 ≥200 cells/mm3, 70% of transmissions occurred when plasmaHIV-1 concentrations exceeded 50,000 copies/mL.Conclusions—Among African heterosexual couples, ART initiation was followed by a 92%reduction in HIV-1 transmission risk, likely due to significantly reduced plasma HIV-1 levels, andwas accompanied by increased self-reported condom use. The highest HIV-1 risk and greatestrelative prevention benefit from ART was among couples in which the HIV-1 infected partner hadCD4 counts <200 cells/mm3 or plasma HIV-1 RNA concentrations >50,000 copies/mL.KeywordsHAART; HIV-1 transmission; HIV-1 discordant couplesIntroductionThe quantity of HIV-1 in plasma is a primary determinant of the risk of HIV-1 transmission.1 Antiretroviral therapy (ART) reduces HIV-1 plasma concentrations to undetectable levelswithin 6 months of initiation in the majority of persons,2, 3 and seminal and cervicovaginalHIV-1 concentrations are also reduced to undetectable levels in most persons on ART.4–7Use of peripartum ART is responsible for the remarkable success in virtually eliminatingmother-to-child HIV-1 transmission in resource-rich settings.8It has been hypothesized that the substantial reduction in the quantity of plasma and genitalHIV-1 in persons initiating ART should translate into markedly reduced risk of HIV-1transmission to sexual partners.9 However, there is a paucity of empiric data on the rate ofsexual HIV-1 transmission from persons receiving ART. A recent meta-analysis of datafrom five studies, some unpublished, found only five cases of HIV-1 transmission in 1098person-years from HIV-1 infected persons receiving ART to sexual partners, consistent withan infection rate between 0.19 and 1.09 per 100 person-years.10 Few studies have comparedsexual behavior before and after ART initiation, an important behavioral consideration. Inaddition, it is unknown how evolving HIV-1 treatment guidelines, which currentlyrecommend ART initiation at CD4 counts between 200 and 350 cells/mm3, 11, 12 relate toHIV-1 transmission risk. Demonstration of HIV-1 transmission benefit for persons initiatingART at CD4 counts at or above current guidelines could provide even greater impetus toprovide ART to populations as a prevention strategy for HIV-1 (e.g., the ‘Test and Treat’concept), in addition to clinical benefits.We examined ART use and HIV-1 transmission risk in a prospective study among 3381African, heterosexual HIV-1 serodiscordant couples, as well as sexual risk and plasmaDonnell et al.Page 2Lancet. Author manuscript; available in PMC 2010 December 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Page 3

HIV-1 concentrations before and after ART initiation. In those not on ART, we measuredHIV-1 transmission rates across a range of CD4 counts and plasma HIV-1 concentrations.MethodsPopulation and ProceduresBetween November 2004 and April 2007, 3408 HIV-1 seropositive persons who were alsoseropositive for herpes simplex virus type 2 (HSV-2) were enrolled in a randomized,double-blind, placebo-controlled, clinical trial of acyclovir HSV-2 suppressive therapy,along with their HIV-1 seronegative heterosexual partners.13 The Partners in PreventionHSV/HIV Transmission Study was conducted at 14 sites in 7 African countries (Botswana,Kenya, Rwanda, South Africa, Tanzania, Uganda, and Zambia). Couples were followed forup to 24 months and follow-up was completed in October 2008. As reported previously,acyclovir HSV-2 suppressive therapy failed to reduce HIV-1 transmission within thecouples, although HIV-1 infected partners who were randomized to acyclovir experienced a73% reduction in incident genital ulcer disease due to HSV-2, an average 0.25 log10 copies/mL reduction in HIV-1 plasma concentrations, and a 16% reduction in the risk of HIV-1disease progression, defined as progression to CD4 count <200 cells/mm3, ART initiation,or death.13, 14Couples were eligible for the trial if they reported ≥3 episodes of vaginal intercourse duringthe three months prior to screening. At the time of enrollment, HIV-1 infected partners were≥18 years of age, HIV-1 and HSV-2 seropositive, had a CD4 count ≥250 cells/mm3 and nohistory of AIDS-defining conditions, and were not receiving ART. HIV-1 uninfectedpartners were ≥18 years of age and HIV-1 seronegative. HIV-1 infected partners were seenmonthly for provision of study drug (acyclovir vs. placebo), evaluation of clinical status, andbehavioral risk assessment. CD4 counts were assessed every six months, and plasma forHIV-1 RNA quantification was collected at baseline, at months 3, 6 and 12 and at the finalstudy visit. HIV-1 uninfected partners were tested quarterly for HIV-1 seroconversion.All participants received pre- and post-test HIV-1 counseling, risk reduction counseling(both individual and couple), free condoms, and treatment of sexually transmitted infections(STIs) according to WHO guidelines throughout the study period. The study protocol wasapproved by the University of Washington Human Subjects Review Committee and ethicalreview committees at the each of the collaborating organizations. All participants providedwritten informed consent.ART initiation among HIV-1 infected partnersOnly couples in which the HIV-1 infected partner was not eligible for ART according tonational ART initiation guidelines were enrolled. At the time the study was conducted,national guidelines generally recommended ART initiation at CD4 counts less than 200–250cells/mm3 or in persons with clinical AIDS. HIV-1 infected persons who met nationalguidelines for initiation of ART during follow-up, as a result of CD4 decline or change inclinical status, were referred to local HIV-1 care clinics to start ART, and counseling and re-referral was done at subsequent visits for those who failed to initiate ART. HIV-1 infectedwomen who became pregnant were referred to antenatal clinics for prevention of mother-to-child transmission services. At quarterly visits, participants were asked whether they hadtaken any antiretroviral medication at any time since the last quarterly visit; for those whohad received ART, the number of days they had taken ART and the medications receivedwere recorded. Participants who initiated ART continued in follow-up with repeat CD4,viral load and behavioral assessments until the maximum of 24 months of follow-up.Donnell et al.Page 3Lancet. Author manuscript; available in PMC 2010 December 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Page 4

Laboratory analysesHIV-1 serologic testing was by dual rapid HIV-1 antibody tests, with positive resultsconfirmed by HIV-1 Western blot. For initially HIV-1 uninfected partners whoseroconverted to HIV-1, analysis of HIV-1 env and gag gene sequences from both membersof the couple was used to determine whether transmission was genetically linked within thepartnership, as previously detailed.13 HSV-2 serostatus was determined by Western blot.15CD4 quantification was performed using standard flow cytometry by local laboratories whoparticipated in external quality assurance. Plasma HIV-1 RNA quantity was tested in batchat the end of the study at the University of Washington using the COBAS TaqMan real-timeHIV-1 RNA assay, version 1.0 (Roche Diagnostics, Indianapolis, IN), with a lower limit ofquantification of 240 copies per mL. Laboratory technicians were blinded to randomizationstatus (acyclovir or placebo) and ART use.Data analysisThe aim of this post-hoc analysis was to assess the effect of ART use by HIV-1 infectedpartners on risk of HIV-1 transmission to their initially-HIV-1 seronegative partners.Twenty-seven couples in which the HIV-1 infected partner’s baseline serology did notconfirm both HIV-1 and HSV-2 infection were excluded.The primary outcome measure was linked HIV-1 transmission – i.e., HIV-1 seroconversionin which viral sequence analysis determined HIV-1 transmission occurred within the studypartnership. Participants who had a genetically unlinked HIV-1 transmission event (i.e., whoacquired HIV-1 from someone outside the study partnership) contributed follow-up timeuntil HIV-1 seroconversion and were censored thereafter.The primary exposure was ART use by HIV-1 infected partners, analyzed as a time-dependent variable. As both HIV-1 serologic testing for HIV-1 seronegative partners andART assessment for HIV-1 infected partners were performed quarterly, any quarter in whichthe HIV-1 infected partner reported any combination ART use was conservativelyconsidered an ‘ART exposed period’ for the HIV-1 uninfected partner, regardless of thenumber of days in that quarter in which the HIV-1 infected partner received ART. Studyquarters in which short-course, mono- or dual-agent ART was used during pregnancy byHIV-1 infected women for prevention of mother-to-child HIV-1 transmission were excludedfrom the analysis because of the limited duration and potency of the regimen. For HIV-1infected partners who initiated combination ART during follow-up, ART use wasconservatively carried forward (i.e. ongoing ART was assumed) regardless of whether theycontinued to report ART use at subsequent visits. ART exposure status for HIV-1 uninfectedpartners was considered unknown if their HIV-1 infected partners were lost to follow-up,and study quarters with unknown ART status were excluded from the analysis.Exact Poisson regression methods were used to calculate the incidence rate ratio andconfidence bounds for HIV-1 transmission among the initially HIV-1 seronegative partners,based on follow-up time in the study and whether or not ART was initiated by their HIV-1infected partners. ART initiation was more common as the study progressed and more likelyto be initiated at lower CD4 counts, and thus estimates of incidence rate ratios were adjustedfor time on study and CD4 count (as above or below 200 cells/mm3). Randomization groupin the clinical trial (i.e., acyclovir or placebo) did not confound the relationship betweenART and HIV-1 transmission risk and thus the risk estimates were not further adjusted forrandomization arm. HIV-1 transmission risk was assessed both overall and in different CD4count strata, with visits prior to ART initiation classified by the lowest prior CD4 count, andvisits after ART initiation classified by the most recent CD4 count prior to ART, to mimicclinical decision-making about ART initiation based on CD4 count. We compared HIV-1Donnell et al.Page 4Lancet. Author manuscript; available in PMC 2010 December 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Page 5

transmission rates from HIV-1 infected partners not on ART, stratified by CD4 count andplasma HIV-1 levels. In this analysis, strata for plasma HIV-1 RNA concentrations weredefined by the highest prior concentration.Sexual behavior was compared before versus after ART initiation for the HIV-1 infectedpersons who initiated ART during follow-up. Conditional logistic regression was used tomodel changes in any unprotected sex, and negative binomial regression with generalizedestimating equations and robust error estimation to model number of sex acts. Both thesemodels were adjusted for time since enrollment in the cohort, as sexual risk behaviorsoverall declined during the study period.13 Plasma HIV-1 concentrations at the most recentvisit prior to initiating ART and at the final study visit were compared using a paired t-testfor those who initiated ART during follow-up. Plasma concentrations below the limit ofquantification were set to 120 copies/mL (half the limit of quantification).Data were analyzed using SAS version 9.20 and LogXact version 8.0.0.Role of the Funding SourceThe authors designed and executed the study, had full access to the raw data, performed allanalyses, wrote the manuscript, and had final responsibility for the decision to submit forpublication. The funder had no role in design, data collection, analysis, interpretation, orwriting of the report.ResultsPopulationA total of 3381 heterosexual HIV-1 serodiscordant couples were eligible for this analysis,2284 (68%) in which the HIV-1 infected partner was female and 1097 (32%) in which theHIV-1 infected partner was male (Table 1). The duration of partnership was 4.6 years orlonger for more than half of the couples. Median sexual frequency was 4 acts per month(IQR 2–8), and 29% of couples reported sex unprotected by condoms during the month priorto enrollment. Among HIV-1 infected participants at enrollment, the median CD4 count was462 cells/mm3 (interquartile range [IQR] 347–631) and median plasma HIV-1 RNAconcentration was 4.1 log10 copies/mL (IQR 3.4–4.7). CD4 counts were lower (median 424vs. 483 cells/mm3, p<0.0001) and plasma HIV-1 RNA concentrations were higher (median4.3 vs. 3.9 log10 copies/mL, p<0.0001) for HIV-1 infected men compared with HIV-1infected women.Follow-up and ART initiationOf the 3381 HIV-1 uninfected persons in the study, 3321 (98%) completed at least onefollow-up assessment of HIV-1 status, contributing 5016 person years of follow-up.Retention was high: 89% of HIV-1 uninfected partners were retained at 12 months and 84%at 24 months. Loss to follow-up of HIV-1 infected partners and quarters where ART wasgiven for PMTCT resulted in exclusion of 186 (4%) person-years of follow-up.ART was initiated by 349 (10%) HIV-1 infected participants, including 9% of women and12% of men (Table 2). The most common ART regimen was stavudine, lamivudine, plusnevirapine (60.7%). Treatment was initiated a median of 13 months after study enrollment.The median CD4 count at ART initiation was 198 cells/mm3, and was not different for menand women. Over half of those who initiated ART had CD4 counts less than 200 cells/mm3at the visit prior to ART initiation, while 33% had CD4 counts between 200 and 350 cells/mm3, 15% had CD4 counts above 350 cells/mm3. Eighteen (34%) of the 53 personsinitiating ART at CD4 counts ≥350 cells/mm3 began combination ART while pregnant. OfDonnell et al.Page 5Lancet. Author manuscript; available in PMC 2010 December 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Page 6

the 349 HIV-1 infected persons who initiated ART, 45 (12.9%) later reported no ART use ata subsequent follow-up visit. HIV-1 susceptible partners were followed for a median of 8.2months (IQR 3.9–12.3) after their HIV-1 infected partners initiated ART.HIV-1 incidence and effect of ART on HIV-1 transmission riskA total of 103 linked HIV-1 transmission events occurred during study follow-up whereART use was known (incidence 2.15 per 100 person-years). An additional 39 unlinkedtransmissions (HIV-1 transmissions from non-study partners) occurred during study follow-up (incidence 0.81 per 100 person-years). Of the 103 linked HIV-1 transmissions, 102occurred in couples in which the HIV-1 infected partner had not yet initiated ART(incidence 2.24 per 100 person-years, Table 2). Only 1 HIV-1 transmission event wasobserved in 349 couples after the HIV-1 infected partners had initiated ART (incidence 0.37per 100 person-years). In analysis adjusting for time since study enrollment and CD4 countstrata, ART use by the HIV-1 infected partner was associated with a 92% reduction in riskof HIV-1 transmission, an effect that was statistically significant (adjusted incidence rateratio [IRR] 0.08, 95% confidence interval [CI] 0.002–0.57, p=0.004).The sole ART-exposed HIV-1 transmission event was a female-to-male transmission inwhich the HIV-1 infected female’s CD4 count was 302 cells/mm3 at enrollment and 201cells/mm3 at the 6 month study visit. At the 9 month study visit, she reported initiating ART18 days earlier, and her male partner tested seronegative for HIV-1 (later testing of hisarchived plasma confirmed that he was HIV-1 RNA PCR negative at that time). Ninety dayslater, at the 12 month study visit, the male partner tested seropositive for HIV-1. The femalepartner’s HIV-1 plasma viral load was 4.72 log10 copies/mL at the 6 month study visit (priorto ART initiation); at the 12 month study visit plasma viral load was undetectable (<240copies/mL) and CD count was 637 cells/mm3.The rate of HIV-1 transmission from HIV-1 infected partners not receiving ART washighest for those with CD4 counts <200 cells/mm3 (8.79 per 100 person-years), and wasrelatively similar across higher CD4 count strata: 2.79, 1.70, and 1.82 per 100 person-yearsfor CD4 counts 200–349, 350–499, and ≥500 cells/mm3, respectively, and there was nostatistically significant difference in these rates (p=0.09). No HIV-1 transmissions were seenamong couples in which the HIV-1 infected partner initiated ART at a CD4 count <200cells/ mm3; this lack of any transmissions in the CD4 <200 cells/mm3 stratum on vs. not onART was statistically significant (adjusted IRR 0, 95% CI 0–0.38, p=0.001). CombiningCD4 strata ≥200 cells/mm3, ART use was associated with reduced HIV-1 transmission risk,although the person-years of follow-up was limited in this strata and this effect was notstatistically significant (adjusted IRR 0.55, 95% CI 0.01–3.24, p=0.93).Plasma HIV-1 concentrations and sexual behavior after ART initiationFor HIV-1 infected participants who initiated ART, the median plasma HIV-1 concentrationprior to ART initiation reduced from 4.88 to <2.38 log10 copies/mL (the limit ofquantification) at the final study visit (p<0.001, n=344 participants who had bothmeasurements), with 70% achieving virologic suppression at the final study visit. Themedian time from ART initiation to the final study visit at which plasma HIV-1 wasmeasured was 7.3 months (IQR 3.4–12.1).As previously detailed,13 reports of high-risk sexual behavior in this cohort decreasedsubstantially after study enrollment, with unprotected sex reported by HIV-1 infectedpartners at only 7% of all follow-up visits. Among those HIV-1 infected partners whoinitiated ART, the proportion of visits at which sex was unprotected by condoms decreasedfurther after ART initiation, from 6.2% before ART to 3.7% of visits after ART (adjustedDonnell et al.Page 6Lancet. Author manuscript; available in PMC 2010 December 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Page 7

OR=0.63, 95% CI 0.41–0.96, p=0.03), an effect that was similar for HIV-1 infected femaleand male participants. Notably, the mean number of sexual acts per month did not changesignificantly after compared to before ART initiation (p=0.6). Further adjustment for sexualactivity unprotected by condoms did not appreciably change the estimate for the effect ofART on reducing HIV-1 transmission risk (IRR 0.088, 95% CI 0.002–0.61, p=0.005).Increased HIV-1 transmission risk at high plasma HIV-1 concentrations with CD4 countsabove 200 cells/mm3For HIV-1 infected partners with CD4 counts above 200 cells/mm3, HIV-1 transmission riskwas highest for those with plasma HIV-1 concentrations >50,000 copies/mL, regardless ofwhether their CD4 count was between 200 and 350 cells/mm3 or was >350 cells/mm3 (Table3). In the 94 HIV-1 transmissions from HIV-1 infected partners who had CD4 counts >200cells/mm3 and who had not initiated ART, 66 (70.2%) occurred from those with plasmaHIV-1 concentrations above 50,000 copies/mL, although they accounted for only 33.4% ofperson-time in follow-up.DiscussionIn this prospective study of almost 3400 heterosexual HIV-1 serodiscordant couples from 7African countries, ART use by the HIV-1 infected partner was accompanied by a 92%reduction in the risk of HIV-1 transmission. An important strength of our study wasphylogenetic linkage of HIV-1 transmissions within the study partnerships, which likelyreduced misclassification of the source of HIV-1 transmission and improved the precision inthe measurement of the effect of ART on HIV-1 risk. These observational data stronglysupport the hypothesis that ART substantially reduces HIV-1 infectiousness andtransmission risk. We found that plasma HIV-1 RNA concentrations decreased significantlyafter ART initiation, likely serving as the mechanism by which ART reduced HIV-1transmission risk, and we found a modest but statistically significant increase in condom useafter ART was initiated. The magnitude of ART effect on HIV-1 transmission risk wasgreatest for persons with CD4 counts <200 cells/mm3, emphasizing the potential synergy ofART for clinical and prevention benefits in persons whose CD4 counts have fallen to 200cells/ mm3.Our results are highly consistent with the findings of a recent meta-analysis that estimated a92% reduction in HIV-1 transmission risk as a result of ART, from 5.64 to 0.46 HIV-1transmissions per 100 person-years.10 Recent mathematical modeling studies have predictedthat universal testing of HIV-1 serostatus and immediate initiation of ART (a strategy called“Test and Treat”) could dramatically reduce new HIV-1 transmissions on a population level.16 To date, little empiric data have been available on the rate of HIV-1 transmission frompersons receiving ART, and our findings provide valuable information for anticipating thedegree of HIV-1 prevention benefit that might be achieved with ART over a two year timeperiod.17In our cohort, the highest rate of HIV-1 transmission occurred from persons with CD4counts <200 cells/mm3, and ART had the greatest absolute benefit in reducing HIV-1transmission risk in this stratum. Less than 50% of persons worldwide with CD4 counts<200 cells/mm3 are currently receiving ART.18, 19 Our data emphasize that an HIV-1transmission benefit would be achieved if coverage of ART was maximized for persons withCD4 counts <200 cells/mm3. Moreover, HIV-1 transmissions were seen in our study acrossall strata of CD4 counts, including a relatively consistent rate of HIV-1 transmission (~2%per year) at CD4 counts >200 cells/mm3. To our knowledge, this is the first study to suggestreduced HIV-1 transmission risk as a result of ART across different ranges of CD4 counts,which indicates that use of ART to dramatically reduce HIV-1 transmission will requireDonnell et al.Page 7Lancet. Author manuscript; available in PMC 2010 December 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Page 8

coverage of those with higher CD4 counts as well as those with CD4 counts <200 cells/mm3. WHO recently recommended raising the threshold for ART initiation for HIV-1treatment from CD4 counts of 200 cell/mm3 to 350 cell/mm3. 12 Our finding that 70% of thetransmissions from HIV-1 infected partners who had CD4 counts >200 cells/mm3 occurredfrom those who also had plasma HIV-1 concentrations >50,000 copies/mL suggeststargeting HIV-1 infected individuals with high plasma HIV-1 concentrations couldmaximize the HIV-1 prevention benefits of ART. Development of inexpensive point of caretests for plasma HIV-1 concentrations could permit real-time plasma HIV-1 testing thatmight allow targeted ART provision to those who have higher CD4 counts and high plasmaHIV-1 concentrations,1, 20 given our and others’ findings about the relationship of plasmaHIV-1 levels to HIV-1 transmission risk.21As with the recent meta-analysis of the effect of ART on HIV-1 transmission risk,10 wefound a low rate of HIV-1 transmission (<0.5% per year) after ART initiation. In the singleHIV-1 transmission event we observed, HIV-1 transmission happened less than four monthsafter ART was begun, and thus it is probable that transmission occurred prior to completeHIV-1 suppression as a result of ART. A 2008 statement from the Swiss FederalCommission for HIV/AIDS argued that HIV-1 infected persons with undetectable plasmaand genital HIV-1 levels as a result of ART can be considered sexually non-infectious.22, 23Little is known about the time course of infectiousness for those who initiate ART, anddurable suppression of both semen and blood HIV-1 levels is not achieved in a fraction oftreated patients.2, 6, 7 Mathematical modeling studies have found that if HIV-1 risk is lowbut non-zero in persons with suppressed HIV-1 levels, population-level increases in HIV-1incidence could result if condom use declined among persons starting ART.22 Our datareinforce the findings of others that ART initiation does not lead to increased sexual activityor decreased condom used in heterosexual couples.17, 24–27 However, the follow-up time onART in this study was short relative to the lifetime duration of ART that will be required ofpersons who start ART. It is essential to obtain reliable information about the comparativelong-term transmission benefits and behavioral risks associated with ART, particularly ARTinitiated at higher CD4 levels. The US National Institutes of Health, through the HIVPrevention Trials Network, has an ongoing five-year clinical trial of ART initiation at CD4counts between 350 and 550 cells/mm2 (versus at <250 cells/mm3), which will be invaluablefor understanding the balance of long-term risks and benefits of ART for treatment andprevention.28In this study, information on ART treatment initiation was obtained by self report, thus thereis potential for misclassification of ART-exposed time, although the one case of HIV-1transmission after ART initiation appeared to be truly in the context of ART use, given thechange in plasma HIV-1 levels observed in the HIV-1 infected partner. Some studyparticipants were unwilling to initiate ART in spite of repeated site staff efforts to linkparticipants to treatment clinics, and thus we observed some follow-up time for participantswith CD4 counts <200 cells/mm3. We did not collect data on the reasons for ART initiationfor those who started ART at CD4 counts >250 cells/mm3, but approximately one-thirdoccurred among pregnant women, potentially reflecting earlier ART initiation for preventionof mother-to-child HIV-1 transmission. We had limited numbers and follow-up for partnersof those initiating ART at CD4 counts >250 cells/mm3 so cannot reliably estimate theimpact of ART on HIV-1 transmission in higher CD4 strata. We also did not haveinformation on ART adherence, although we did see substantial declines in plasma HIV-1RNA levels with 70% of persons with undetectable levels at a median of 7 months afterART initiation. All HIV-1 infected partners in this study were HSV-2 seropositive; however,HSV-2 is common among persons with HIV-1 worldwide (seroprevalence 50–90%), andthus this study entry requirement is unlikely to limit the generalizability of our findings.Donnell et al.Page 8Lancet. Author manuscript; available in PMC 2010 December 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript